Paclitaxel is a natural product extracted from the bark of Pacific yew trees, Taxus brevifolia and the active constituent of the anticancer agent TAXOL®. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis. It is used clinically against a number of human cancers. It is an important cancer agent both therapeutically and commercially. Numerous clinical trials are in progress to expand and increase the utility of this agent for the treatment of human proliferative diseases. The results of TAXOL® clinical studies have been reviewed by numerous authors. A very recent compilation of articles by a number of different authors is contained in the entire issue of Seminars on Oncology 1999, 26 (1, Suppl 2). Other examples are such as by Rowinsky et al. in TAXOL®: A Novel Investigational Antimicrotubule Agent, J. Natl. Cancer Instl, 82: pp 1247–1259, 1990; by Rowinsky and Donehower in “The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics,” Pharmac. Ther., 52:35–84, 1991; by Spencer and Faulds in “Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer,” Drugs, 48 (5) 794–847, 1994; by K. C. Nicolaou et al. in “Chemistry and Biology of TAXOL®,” Angew. Chem., Int. Ed. Engl., 33: 15–44, 1994; by F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, V. Valero in the book “Taxane Anticancer Agents Basic Science and Current Status” edited by Gunda I. Georg, Thomas T. Chen, Iwao Ojima, and Dolotrai M. Vyas, 1995, American Chemical Society, Washington, D.C., 31–57; by Susan G. Arbuck and Barbara Blaylock in the book “TAXOL® Science and Applications” edited by Mathew Suffness, 1995, CRC Press Inc., Boca Raton, Fla., 379–416; and also in the references cited therein.
A semi-synthetic analog of paclitaxel named docetaxel has also been found to have good antitumor activity and is the active ingredient of the commercially available cancer agent TAXOTERE®. See, Biologically Active Taxol Analogues with Deleted A-Ring Side Chain Substituents and Variable C-2′ Configurations, J. Med. Chem., 34, pp 1176–1184 (1991); Relationships between the Structure of Taxol Analogues and Their Antimitotic Activity, J. Med. Chem., 34, pp 992–998 (1991) incorporated herein by reference. A review of the clinical activity of TAXOTERE® by Jorge E. Cortes and Richard Pazdur has appeared in Journal of Clinical Oncology 1995, 13(10), 2643 to 2655. The structures of paclitaxel and docetaxel are shown below along with the conventional numbering system for molecules belonging to the class; such numbering system is also employed in this application.
paclitaxel (TAXOL®): R=Ph; R1=acetyldocetaxel (TAXOTERE®): R=t-butoxy; R1=hydrogen
Ample evidence that paclitaxel has no oral activity can be found within the following quote from PCT patent application WO 98/53811 by inventors Samuel Broder, Kenneth L. Duchin and Sami Selim and the references cited within the quote, which says: “Paclitaxel is very poorly absorbed when administered orally (less than 1%); see Eiseman et al., Second NCI Workshop on Taxol and Taxus (September 1992); Suffness et al., in TAXOL Science and Applications (CRC Press 1995). Eisemann et al., indicate that paclitaxel has a bioavailability of 0% upon oral administration and Suffness et al., report that oral dosing with paclitaxel did not seem possible since no evidence of antitumor activity was found on oral administration up to 160 mg/kg/day. Moreover, no effective method has been developed to enable the effective administration of oral paclitaxel (i.e., a method of increasing the oral bioavailability of paclitaxel) or of other oral taxanes or paclitaxel analogs such as docetaxel which exhibit antitumor activity. For this reason, paclitaxel has not until now been administered orally to human patients, and certainly not in the course or treating paclitaxel-responsive diseases.” Another report by J. Terwogt et al., from the Lancet, Jul. 25, 1998, vol. 352 page 285 also describes the low bioavailability to doses as high as 160 mg/kg/inj in murine (mouse) tumor models (sc M109) without signs of any efficacy and have concluded, like Suffness, that further dosing would not provide efficacy even though toxic doses were not reached. Furthermore, our own attempts to demonstrate activity for orally administered paclitaxel against human tumor xenografts implanted in either athymic mice or athymic rates have to date been unsuccessful.
The present invention provides for the enzymatically resolution racemic mixtures of particular effective water soluble C-4 taxane analogs disclosed in copending U.S. patent application Ser. No. 09/712,352, incorporated herein by reference, which have oral activity and thus would have utility against proliferative diseases after oral administration. Some of the background art pertaining to this invention are shown below.
Certain taxane derivatives with modifications at the C-4 hydroxy group have been described in the art.
U.S. Pat. No. 5,808,102 to Poss et al., and PCT Published Patent Application No. WO 94/14787 contain descriptions of taxane analogs with modifications at the C-4 positions.
Gunda I. Georg et al., describe the synthesis of a C-4 ester analog in Tetrahedron Letters, 1994, 35(48) 8931–8934.
S. Chen et al., describe the synthesis of a C-4 cyclopropyl ester analog in Journal of Organic Chemistry 1994, 59(21), 6156–8.
U.S. Pat. No. 5,840,929 to Chen, Shu-Hui covering the C4 methoxy ether derivatives issued on Nov. 24, 1998.
Chen, Shu-Hui. First synthesis of C-4 methyl ether paclitaxel analogs and the unexpected reactivity of 4-deacetyl-4-methyl ether baccatin III. Tetrahedron Lett. 1996, 37(23), 3935–3938.
The following reference discusses a number of C-4 ester or carbonate analogs: Chen, Shu-Hui; Wei, Jian-Mei; Long, Byron H.; Fairchild, Craig A.; Carboni, Joan; Mamber, Steven W.; Rose, William C.; Johnston, Kathy; Casazza, Anna M.; et al. Novel C-4 paclitaxel (Taxol) analogs: potent antitumor agents. Boorg. Med. Chem. Lett. 1995, 5(22), 2741–6.
The preparation of C-4 aziridinyl carbamate analogs has been described in: Chen, Shu-Hui; Fairchild, Craig; Long, Byron H. Synthesis and Biological Evaluation of Novel C-4 Aziridine-Bearing Paclitaxel (Taxol) Analogs. J. Med. Chem. 1995, 38(12), 263–7.
The following papers describe reactions or transformations which are described as of C-4 analog preparation:
A new method to modify the C-4 position of 10-deacetylbaccatin III. Uoto, Kouichi; Takenoshita, Haruhiro; Ishiyama, Takashi; Terasawa, Hirofumi; Soga, Tsunehiko, Chem. Pharm. Bull. 1997, 45(12), 2093–2095.
Samaranayake, Gamini; Neidigh, Kurt A.; Kiingston, David G. I. Modified taxols, 8. Deacylation and reacylation of Baccatin III. J. Nat. Prod. 1193, 56(6), 884–98.
Datta, Apurba; Jayasinghe, Lalith R.; Georg, Gunda I. 4-Deacetyltaxol and 10-Acetyl-4-deacetyltaxotere: Synthesis and Biological Evaluation. J. Med. Chem. 1994, 37(24), 4258–60.
Inspite of the above-mentioned examples of C-4 analogs or methodology to prepare them, no evidence of orally active C-4 analogs has been supplied. The present invention provides a method of resolving racemic mixtures of C-4 analogs which have oral activity.
The following references describe methods or possible methods for orally active taxanes.
Methods for administering taxanes in the presence of modulators have been reported to increase the amount of taxanes in the plasma after oral administration: Terwogt, Jetske M. Meerum; Beijnen, Jos H.; Ten Bokkel Huinink, Wim W.; Rosing, Hilde; Schellens, Jan H. M. Coadministration of cyclosporin enables oral therapy with paclitaxel. Lancet (1998), 352 (9124), 285.
Terwogt, Jetski M. Meerum; Malingre, Mirte M.; Beijnen, Jos H.; Huinink, Wim W. ten Bokkel; Rosing, Hilde; Koopman, Franciska J.; Van Tellingen, Olaf; Swart, Martha; Schellens, Jan H. M. Co-administration of oral cyclosporin A enables oral therapy with paclitaxel. Clin. Cancer Res. (1990), 5(11), 3379–3384.
Hansel, Steven B. A method of making taxanes orally bioavailable by coadministration with cinchonine. PCT Int. Appl. WO 97/27855 published Aug. 7, 1997.
Broder, Samuel; Duchin, Kenneth L.; Selim, Sami. Method and compositions for administering taxanes orally to human patients using a cyclosporin to enhance bioavailability. PCT Int. Appl. WO 98/53811 published Dec. 3, 1998. These reports contain no antitumor efficacy data but the presence of taxanes in the plasma is extrapolated to show their potential for anticancer utility.
At least one report of oral activity of prodrugs in preclinical animal modes has appeared in the prior art: Scola, Paul M.; Kadow, John F.; Vyas, Dolatrai M. Preparation of paclitaxel prodrug derivatives. Eur. Pat. Appl. EP 747385 published Dec. 11, 1996. The oral bioavailability of the prodrug which had oral efficacy was not disclosed an no further reports of these compounds progressing to man have appeared.
Very recently, an abstract describing a taxane analog (IDN-5109) with oral activity against tumors in mice was disclosed at the American Association of Cancer Researchers in Philadelphia in 1999. The reference for the abstract is: Pratesi G. Polizzi D, Totoreto M, Riva A, Bombardelli E, Zunino F: IND5109 a new taxane active after oral administration. Proc Am Assoc Cancer Res 1999 40 Abs 1905, Istituto Nazionale Tumori, 20133 Milan and Indena SpA, 20139, Milan, Italy. The structure of this compound is quite different than compounds described in the present invention. Unlike the compounds encompassed by the present invention, IDN-1509 is derived from 14-betahydroxy baccatin III and has an acetate on the hydroxy group at the C-4 position.
Two references on the activity of this compound are included for completeness.
Nicoletti M L, Rossi C, Monardo C, Stura S, Morazzoni P, Bombardelli E, Valoti G, Giavazzi R.: Antitumor efficacy of the paclitaxel analogue, IDN5109, on human ovarian cacinoma xenografts with different sensitivity to the paclitaxel. Proc Am Assoc Cancer Res 1999 40 Abs 1910 [Evals+citations].
Polizzi, Donatella; Pratesi, Graziella; Tortoreto, Monica; Supino, Rosanna; Riva, Antonella; Bombardelli, Ezio; Zunino, Franco. A novel taxane with improved tolerability and therapeutic activity in a panel of human tumor xenografts. Cancer Res. 1999, 59(5), 1036–1040.
Paclitaxel is a highly schedule dependent drug that benefits traditionally from prolonged tumor exposure times. This relates to paclitaxel's mechanism of action as taxanes only recognize and bind to the polymerized state of tubulin which occurs only during a brief period of the cancer cell cycle. The currently used intravenous infusions (1–3 hours) are now readily accepted and efficacious and preclude the routine use of protracted (>24 hours) continuous schedules. However, an oral taxane may provide a compliant and cost effective way of accomplishing such extended duration of exposure. Recently, clinical utility has also been demonstrated using repetitive once weekly administrations of moderate (i.e., other than maximally tolerated) doses of TAXOL® and an oral taxane would be ideal for such protracted regimens. Other purported clinical indications for taxanes use (e.g., rheumatoid arthritis, multiple sclerosis) would also benefit from the availability of an oral taxane. An orally administered effective taxane would offer both an attractive alternative from the parenteral from the format of current clinical taxane usage, and a potential therapeutic advantage because of the many avenues of scheduling yet to be investigated.
Thus, it is clear there is a great need to provide taxanes in a pure, highly resolved form with both good oral bioavailability and good oral efficacy, which are comparable to paclitaxel administered parenterally.